Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Molecular Formula: C8H14N2O2
CAS Number: 102767-28-2
Brands: Keppra
Special Alerts:
[UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.
The drugs included in the analyses include (some of these drugs are also available in generic form):
Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Levetiracetam (marketed as Keppra)
Oxcarbazepine (marketed as Trileptal)
Pregabalin (marketed as Lyrica)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
Zonisamide (marketed as Zonegran)
For more information visit the FDA website at: and .
[UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.
For more information visit the FDA website at: and .
[Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.
Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.
The drugs included in the analyses include (some of these drugs are also available in generic form):
Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Levetiracetam (marketed as Keppra)
Oxcarbazepine (marketed as Trileptal)
Pregabalin (marketed as Lyrica)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
Zonisamide (marketed as Zonegran)
Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. For more information visit the FDA website at: and .
REMS:
FDA approved a REMS for levetiracetam to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
Anticonvulsant; a pyrrolidine derivative.1 2 3 5
Uses for Levetiracetam
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Seizure Disorders
Management (in combination with other anticonvulsants) of partial seizures in adults with epilepsy.1 2 3
Levetiracetam Dosage and Administration
Administration
Oral Administration
Administer orally twice daily without regard to meals.1
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Adults
Seizure Disorders
Partial Seizures
Oral
Initially, 500 mg twice daily.1 2 3
If response is inadequate, dosage may be increased by 1 g daily at 2-week intervals.1 2
Some clinicians reportedly initiate therapy with dosages of 2–4 g daily.3
Dosages >3 g daily may not be associated with increased therapeutic benefit.1 2
Do not discontinue abruptly;1 withdraw gradually by reducing dosage by 1 g daily at 2-week intervals.5 (See Discontinuance of Levetiracetam under Cautions.)
Prescribing Limits
Adults
Seizure Disorders
Partial Seizures
Oral
Maximum 3 g daily recommended by the manufacturer.1
Special Populations
Renal Impairment
Modify dosage according to the degree of impairment based on patient’s measured or estimated Clcr.1 2 (See Table 1.)
Renal Function | Clcr (mL/minute) | Dosage |
|---|---|---|
Normal | >80 | 500–1500 mg every 12 hours |
Mild | 50–80 | 500–1000 mg every 12 hours |
Moderate | 30–50 | 250–750 mg every 12 hours |
Severe | <30 | 250–500 mg every 12 hours |
ESRD patients using dialysis | – | 500–1000 mg every 24 hours; following dialysis, a 250- to 500-mg supplemental dose is recommended |
Geriatric Patients
Select dosage carefully1 2 and consider monitoring renal function during therapy.1
Cautions for Levetiracetam
Contraindications
Known hypersensitivity to levetiracetam or any ingredient in the formulation.1 2
Warnings/Precautions
Warnings
Nervous System Effects
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Possible adverse neuropsychiatric effects are classified into 3 categories: somnolence and fatigue; coordination difficulties; behavioral changes.1 2
Somnolence, asthenia, and coordination difficulties occur most frequently within first 4 weeks of treatment.1 2
Psychotic manifestations and hallucinations reported rarely.1 2
Possible behavioral symptoms (e.g., agitation, hostility, anxiety, apathy, emotional lability, depersonalization, depression, aggression, anger, irritability).1
Discontinuance of Levetiracetam
Abrupt withdrawal may result in increased seizure frequency or status epilepticus.1 2 (See Partial Seizures under Dosage and Administration.)
General Precautions
Hematologic Effects
Minor decreases in total mean erythrocyte count, mean hemoglobin, and mean hematocrit possible.1
Possible leukopenia, neutropenia, pancytopenia with myelosuppression in some cases, and thrombocytopenia.1
Hepatic Effects
No meaningful changes in liver function test results in controlled studies.1
Possible Prescribing and Dispensing Errors
Ensure accuracy of prescription; similarity in spelling of Keppra (levetiracetam) and Kaletra (fixed combination of lopinavir and ritonavir, both antiretroviral agents) may result in errors.7
Specific Populations
Pregnancy
Category C.1
Keppra Pregnancy Registry at 888-537-7734 or North American Antiepileptic Drug Pregnancy Registry at 888-233-2334.1
Lactation
Distributed into milk.1 Discontinue nursing or the drug because of potential risk in nursing infant.1
Pediatric Use
Safety and efficacy not established in children <16 years of age.1 2
Geriatric Use
No substantial differences in safety relative to younger adults; insufficient experience in patients ≥65 years of age to determine whether efficacy is similar.1 2
Renal Impairment
Dosage adjustment recommended for patients with decreased Clcr.1 2 (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Somnolence, asthenia, headache, infection, dizziness, pain, pharyngitis.1 2
Interactions for Levetiracetam
Not a high-affinity substrate for or inhibitor of CYP isoenzymes.1 2
Drugs Affecting Hepatic Microsomal Enzymes
Pharmacokinetic interaction unlikely.1 2
Protein-bound Drugs
Pharmacokinetic interaction unlikely.1 2
Specific Drugs
Drug | Interaction | Comments |
|---|---|---|
Anticonvulsants (e.g., carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid) | Pharmacokinetic interaction unlikely1 2 | |
Digoxin | Pharmacokinetic interaction unlikely1 2 | |
Oral contraceptives | Pharmacokinetic interaction unlikely1 2 | |
Probenecid | No effect on levetiracetam pharmacokinetics, but steady-state plasma concentrations of principal inactive metabolite of levetiracetam approximately doubled because of 60% reduction in renal clearance1 2 | Clinically unimportant5 |
Warfarin | Pharmacokinetic interaction unlikely1 2 |
Levetiracetam Pharmacokinetics
Absorption
Bioavailability
Rapidly and almost completely absorbed (nearly 100% bioavailable) following oral administration, with peak plasma concentrations attained in approximately 1 hour.1
Commercially available tablets and oral solution are bioequivalent.1
Food
Food does not affect bioavailability but delays time to peak plasma concentration by 1.5 hours and decreases peak plasma concentration by 20%.1
Distribution
Extent
Distributed into milk.1
Plasma Protein Binding
<10%.1
Elimination
Metabolism
Not extensively metabolized.1 About 24% of an administered dose is metabolized to an inactive metabolite by hydrolysis of the acetamide group; metabolism is not dependent on CYP isoenzymes.1
Elimination Route
Excreted principally as unchanged drug (66%) in urine.1
Clearance is correlated with Clcr.1
Half-life
6–8 hours.1
Special Populations
In patients with renal impairment, clearance is reduced by 40, 50, and 60% in patients with mild, moderate, and severe renal impairment, respectively.1 In patients with end-stage renal disease, clearance is reduced by about 70%; hemodialysis removes about 50% of body stores of levetiracetam.1 (See Renal Impairment under Dosage and Administration.)
In patients with severe hepatic impairment (Child Pugh class C), total body clearance is reduced by 50%, principally due to decreased renal clearance; pharmacokinetics unchanged in patients with mild (Child Pugh class A) to moderate (Child Pugh class B) hepatic impairment.1
In geriatric patients with Clcr of 30–74 mL/minute, total body clearance is reduced by 38% and half-life increased by 2.5 hours, but no pharmacokinetic differences related solely to age observed.1 2
In pediatric patients 6–12 years of age, body weight-adjusted apparent clearance is approximately 40% higher than in adults.1
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15–30°C).1
Solution
25°C (may be exposed to 15–30°C).1
Actions
Structurally unrelated to other currently available anticonvulsants.1 2 3 5
Mechanism of anticonvulsant action is not known.1 2 4
Protection observed against secondarily generalized activity from focal seizures induced by 2 chemoconvulsants known to induce seizures that mimic some features of human complex partial seizures with secondary generalization.1 2
Demonstrated inhibitory properties in the kindling model in rats, another model of human complex partial seizures.1 2 4
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Provide copy of manufacturer’s patient information.1
Risk of adverse neuropsychiatric effects (e.g., somnolence, fatigue, dizziness, coordination difficulties, behavioral changes), especially during the initial weeks of therapy.1 2
Risk of drowsiness; avoid driving, operating machinery, or performing hazardous tasks until effects on individual are known.1 2 5
Importance of adhering to prescribed directions for use.1
Importance of not abruptly discontinuing therapy.1 2
Use in combination with other anticonvulsants, not as monotherapy.1 2
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 Importance of clinicians informing women about existence of and encouraging enrollment in pregnancy registries. (See Pregnancy under Cautions.)
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illness (e.g., renal disease).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 100 mg/mL | Keppra Oral Solution (dye-free; with glycerin and parabens) | UCB Pharma |
Tablets, film-coated | 250 mg | Keppra (scored) | UCB Pharma | |
500 mg | Keppra (scored) | UCB Pharma | ||
750 mg | Keppra (scored) | UCB Pharma |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Keppra 100MG/ML Solution (UCB PHARMA): 473/$437.98 or 1419/$1,306.04
Keppra 1000MG Tablets (UCB PHARMA): 60/$570.02 or 180/$1,690.05
Keppra 250MG Tablets (UCB PHARMA): 10/$51.99 or 30/$129.97
Keppra 500MG Tablets (UCB PHARMA): 30/$149.99 or 90/$429.97
Keppra 750MG Tablets (UCB PHARMA): 30/$189.99 or 90/$549.95
Keppra XR 500MG 24-hr Tablets (UCB PHARMA): 60/$245.98 or 180/$699.97
Keppra XR 750MG 24-hr Tablets (UCB PHARMA): 60/$349.98 or 180/$1,019.91
Levetiracetam 100MG/ML Solution (ROXANE): 473/$259.99 or 1419/$719.96
Levetiracetam 1000MG Tablets (LUPIN PHARMACEUTICALS): 60/$209.99 or 180/$599.98
Levetiracetam 250MG Tablets (LUPIN PHARMACEUTICALS): 60/$23.99 or 120/$37.97
Levetiracetam 500MG Tablets (LUPIN PHARMACEUTICALS): 30/$29.99 or 90/$59.97
Levetiracetam 750MG Tablets (LUPIN PHARMACEUTICALS): 60/$34.99 or 120/$57.97
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. UCB Pharma, Inc. Keppra (levetiracetam) tablets and oral solution prescribing information. Smyrna, GA; 2004 Nov.
2. UCB Pharma. Keppra (levetiracetam) tablets product monograph. Smyrna, GA; 2002.
3. Anon. Two new drugs for epilepsy. Med Lett Drugs Ther. 2000; 42:33-5. [PubMed 10803174]
4. Haria M, Balfour JA. Levetiracetam. CNS Drugs. 1997; 7:159-64.
5. UCB Pharma, Smyrna, GA: Personal communication.
6. Krakow K, Walker M, Otoul C et al. Long-term continuation of levetiracetam in patients with refractory epilepsy. Neurology. 2001; 56:1772-4. [IDIS 466256] [PubMed 11425954]
7. Magnus L. Dear healthcare professional letter: Dispensing error alert. Smyrna, GA: UCB Pharma, Inc; 2003 Sep.
8. Institute for Safe Medication Practices. What’s in a name? Ways to prevent dispensing errors linked to name confusion. ISMP Medication Safety Alert!. Huntingdon Valley, PA; 2002 Jun 12.
More Levetiracetam resources
- Levetiracetam Side Effects (in more detail)
- Levetiracetam Dosage
- Levetiracetam Use in Pregnancy & Breastfeeding
- Drug Images
- Levetiracetam Drug Interactions
- Levetiracetam Support Group
- 101 Reviews for Levetiracetam - Add your own review/rating
- Levetiracetam Professional Patient Advice (Wolters Kluwer)
- Levetiracetam Prescribing Information (FDA)
- Levetiracetam MedFacts Consumer Leaflet (Wolters Kluwer)
- Keppra Consumer Overview
- Keppra Prescribing Information (FDA)
- Keppra XR Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)
- levetiracetam Advanced Consumer (Micromedex) - Includes Dosage Information
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